Neuropathic pain and inflammatory pain differ in their etiology, pathophysiology and responses to treatment with different pharmaco-therapeutical agents. Injuries usually lead to a combination of both types of pain due to the involvement of both nerve fibers and accompanying inflammation. Most of the time one component might dominate over the other making a definitive diagnosis difficult. Moreover, the present treatment modalities for these two types of pain are entirely different making it difficult to completely alleviate the pain by one treatment. Severe acute pain responds to μ opioid receptor agonists (morphine) and NMDA receptor antagonists (ketamine); chronic inflammatory pain responds to cycloxygenase inhibitors (Bextra™, Celebrex™) and prostaglandin inhibitors (acetaminophen); neuropathic pain responds to antiepileptic medications (carbamazepine) and drugs of still not completely known actions (gabapentin).
Pain induces elevated levels of molecules downstream of adenylyl cyclases in neuronal populations, in dorsal root ganglion neurons, spinal dorsal horn and anterior cingulate cortex (ACC) that are activated in pain transmission. These molecules include transcription factor pCREB (Anderson and Seybold, 2000; Kawasaki et al., 2004, Ma and Quirion, 2001) and immediate early genes Egr-1 (Wei et al., 2000, Ko et al., 2005) and Arc (Li et al., 2004). Adenylyl cyclases (ACs) are known as coincidence detectors in neurons due to their specific interaction with G-proteins, NMDA receptors, voltage-dependent calcium channels and μ opioid receptors at the neuronal membrane. The role of adenylyl cyclases was shown to be important in behavioral sensitization associated with chronic inflammation (Wei et al., 2002b). Common signaling pathways induced by the activation of adenylyl cyclases have demonstrated their capability as key initiator molecules in memory and inflammatory pain (Woolf and Salter, 2000); (Kandel, 2001, Nestler, 2001 and Zhuo, 2004) and their contribution to NMDA receptor-dependent synaptic potentiation lasting several hours (Wong et al., 1999).
Of the ten different isoforms of ACs that have been identified (Xia and Storm, 1997), AC1 is a calcium calmodulin (CaM)-stimulated AC present in the brain and spinal cord which is highly neuron-specific. Mice lacking AC1 and 8 were shown to lack long term memory for passive avoidance, contextual and spatial memory ((Wong et al., 1999, Wu et al., 1995). Mice lacking AC1 and 8 also showed reduced chronic inflammatory pain in mice (Wei et al., 2002b). Thus, the neuronal membrane bound ACs are important membrane-bound enzymes that can modulate the downstream cascade of molecules that eventually regulate gene transcription and mediate their effect through the expressed proteins either in nerve conduction or in synaptic plasticity changes. A comparative study of the effect of AC1 and AC8 was conducted to identify the more effective isoform to target. Mice lacking AC1 were found to have a superior effect on subcutaneous inflammatory pain (Wei et al, 2002), acute muscle pain, chronic muscle pain and neuropathic pain.
Given the foregoing, it would be desirable to develop a protocol that down-regulates AC1 to yield a treatment which targets pain of both neural and non-neural origin.